Activin Signaling Targeted by Insulin/dFOXO Regulates Aging and Muscle Proteostasis in Drosophila

Bai, Hua; Kang, Ping; Hernández, Ana; Tatar, Marc

doi:10.1371/journal.pgen.1003941

Cited by 178 publications

(231 citation statements)

References 78 publications

(116 reference statements)

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“…Using a cutoff of fourfold enrichment over input, we identified ∼2,200 genes that were bound by dFOXO (Dataset S1). The number of targets agrees well with previously reported dFOXO ChIP studies (20)(21)(22)(23). Comparisons with the previous ChIP studies of dFOXO binding indicate that the genes bound in this model most closely resemble those found in starved larva or the adult fat body (Dataset S2) (20)(21)(22)(23).…”

Section: Resultssupporting

confidence: 89%

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FOXO regulates RNA interference in Drosophila and protects from RNA virus infection

Spellberg

Marr

2015

Proc. Natl. Acad. Sci. U.S.A.

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Small RNA pathways are important players in posttranscriptional regulation of gene expression. These pathways play important roles in all aspects of cellular physiology from development to fertility to innate immunity. However, almost nothing is known about the regulation of the central genes in these pathways. The forkhead box O (FOXO) family of transcription factors is a conserved family of DNAbinding proteins that responds to a diverse set of cellular signals. FOXOs are crucial regulators of cellular homeostasis that have a conserved role in modulating organismal aging and fitness. Here, we show that Drosophila FOXO (dFOXO) regulates the expression of core small RNA pathway genes. In addition, we find increased dFOXO activity results in an increase in RNA interference (RNAi) efficacy, establishing a direct link between cellular physiology and RNAi. Consistent with these findings, dFOXO activity is stimulated by viral infection and is required for effective innate immune response to RNA virus infection. Our study reveals an unanticipated connection among dFOXO, stress responses, and the efficacy of small RNA-mediated gene silencing and suggests that organisms can tune their gene silencing in response to environmental and metabolic conditions.O rganisms must be able to respond to changing conditions to survive. Radical changes in environment or metabolism can induce cellular stress signaling pathways meant to help the cell return to a normal range of function. Whereas there are dedicated transcriptional response pathways to deal with specific individual stresses such as heat shock (HSF) (1) or heavy metals (MTF-1) (2), the forkhead box O (FOXO) pathway has emerged as a general stress responsive transcription factor. Although initially characterized as downstream targets of insulin signaling, it is now clear that the FOXOs respond to multiple cellular stress signaling pathways including nutrient deprivation, oxidative stress, mitochondrial dysfunction, DNA damage, bacterial infection, and other cellular stress signals (3, 4).The FOXO family of transcription factors is conserved from Caenorhabditis elegans to humans. Invertebrates have a single FOXO gene: daf-16 in worms and dFOXO in Drosophila (5, 6). In mammals, the four FOXO genes (FOXO1, FOXO3, FOXO4, and FOXO6) have diversified, with some factors having a stressspecific response (7-10). Therefore, invertebrates offer a particularly attractive system for understanding FOXO function because the single isoform is responsible for all of the roles of the four mammalian FOXOs.Small noncoding RNA pathways are capable of regulating gene expression in a sequence-specific manner (11). Effector complexes called RNA-induced silencing complexes (RISC) containing small single-stranded RNAs bound to Argonaute proteins find target mRNAs and posttranscriptionally prevent their expression. Three major small RNA pathways have been identified in animal cells, the microRNA (miRNA) pathway, the small interfering RNA pathway (siRNA), and PIWI RNA (piRNA) pathways, each contain uni...

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Section: Resultssupporting

confidence: 89%

“…1A). Using the same approach, similar sequences were identified in three of the four previous studies (20)(21)(22)(23) (Fig. S1).…”

Section: Resultsmentioning

confidence: 65%

FOXO regulates RNA interference in Drosophila and protects from RNA virus infection

Spellberg

Marr

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Flies with babo knockdown in muscle lived about 20% longer than wild‐type, and pathway analysis of FOXO gene targets revealed enrichment of processes involved in postembryonic development, neuron differentiation, axonogenesis, and regulation of transcription and growth (Bai et al., 2013), similar to the terms we observed here (Table S3). …”

Section: Resultssupporting

confidence: 89%

“…Downregulation of activin signaling by forkhead transcription factor (FOXO) in muscle tissues of flies has been shown to improve muscle performance, reduce secretion of insulin peptides from brain, and extend lifespan (Bai, Kang, Hernandez & Tatar, 2013). Flies with babo knockdown in muscle lived about 20% longer than wild‐type, and pathway analysis of FOXO gene targets revealed enrichment of processes involved in postembryonic development, neuron differentiation, axonogenesis, and regulation of transcription and growth (Bai et al., 2013), similar to the terms we observed here (Table S3).…”

Section: Resultsmentioning

confidence: 99%

Comparative transcriptomics across 14 Drosophila species reveals signatures of longevity

Avanesov

Porter

et al. 2018

Aging Cell

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SummaryLifespan varies dramatically among species, but the biological basis is not well understood. Previous studies in model organisms revealed the importance of nutrient sensing, mTOR, NAD/sirtuins, and insulin/IGF1 signaling in lifespan control. By studying life‐history traits and transcriptomes of 14 Drosophila species differing more than sixfold in lifespan, we explored expression divergence and identified genes and processes that correlate with longevity. These longevity signatures suggested that longer‐lived flies upregulate fatty acid metabolism, downregulate neuronal system development and activin signaling, and alter dynamics of RNA splicing. Interestingly, these gene expression patterns resembled those of flies under dietary restriction and several other lifespan‐extending interventions, although on the individual gene level, there was no significant overlap with genes previously reported to have lifespan‐extension effects. We experimentally tested the lifespan regulation potential of several candidate genes and found no consistent effects, suggesting that individual genes generally do not explain the observed longevity patterns. Instead, it appears that lifespan regulation across species is modulated by complex relationships at the system level represented by global gene expression.

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“…In addition to Actβ, another activin ligand Daw also targets Babo/dSmad2 and regulates systemic carbohydrate metabolism and the aging process, probably via modulation of dILP2 secretion (28,29). Although Daw is expressed in the muscle, we do not believe that Daw is involved in mitochondrial synchrony between muscle and fat body because Daw knockdown in complex I-perturbed muscles fails to restore normal levels of TG storage.…”

Section: Discussionmentioning

confidence: 92%

Activin signaling mediates muscle-to-adipose communication in a mitochondria dysfunction-associated obesity model

Song

Owusu-Ansah

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Mitochondrial dysfunction has been associated with obesity and metabolic disorders. However, whether mitochondrial perturbation in a single tissue influences mitochondrial function and metabolic status of another distal tissue remains largely unknown. We analyzed the nonautonomous role of muscular mitochondrial dysfunction in Drosophila. Surprisingly, impaired muscle mitochondrial function via complex I perturbation results in simultaneous mitochondrial dysfunction in the fat body (the fly adipose tissue) and subsequent triglyceride accumulation, the major characteristic of obesity. RNA-sequencing (RNA-seq) analysis, in the context of muscle mitochondrial dysfunction, revealed that target genes of the TGF-β signaling pathway were induced in the fat body. Strikingly, expression of the TGF-β family ligand, Activin-β (Actβ), was dramatically increased in the muscles by NF-κB/Relish (Rel) signaling in response to mitochondrial perturbation, and decreasing Actβ expression in mitochondrial-perturbed muscles rescued both the fat body mitochondrial dysfunction and obesity phenotypes. Thus, perturbation of muscle mitochondrial activity regulates mitochondrial function in the fat body nonautonomously via modulation of Activin signaling.mitochondrial synchrony | Activin-β | complex I perturbation | NF-κB/Relish | lipid metabolism I ndividual organs in a multicellular organism, besides performing their respective roles, must communicate with other organs to maintain systemic homeostasis. The central nervous system (CNS) in particular integrates information regarding the status of peripheral metabolic processes via hormonal signaling and directs energy homeostasis and feeding behavior (1). In addition, metabolic changes in a peripheral organ can affect the physiology of other peripheral organs (2, 3). The skeletal muscle system, which is newly recognized as playing endocrine-related roles, produces myokines after exercise to target other metabolic organs (liver, adipose tissue, pancreas, gut, and bone) and modulates systemic energy homeostasis (4).Mitochondria are semiautonomous organelles that integrate multiple physiological signals. Growing evidence indicates that mitochondrial alterations in one organ leads to abnormalities in biological processes in distal organs through hormonal signaling (5, 6). In addition to exercise, which induces mitochondrial activity and improves muscle performance, mitochondrial perturbationassociated muscle injury is also sufficient to modulate functions of other organs and change systemic outcomes via myokine production. For example, in mammals, mitochondrial dysfunction due to disruption of autophagic function in skeletal muscles results in elevated production of muscular FGF21 that triggers browning of white adipose tissue and increases lipid mobilization (7). Further, in Drosophila, mild mitochondrial distress in adult muscles delays aging via an increase of muscular ImpL2 production and remote suppression of insulin signaling in the fat body and brain (8). Despite these examples, molecula...

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Activin Signaling Targeted by Insulin/dFOXO Regulates Aging and Muscle Proteostasis in Drosophila

Cited by 178 publications

References 78 publications

FOXO regulates RNA interference in Drosophila and protects from RNA virus infection

FOXO regulates RNA interference in Drosophila and protects from RNA virus infection

Comparative transcriptomics across 14 Drosophila species reveals signatures of longevity

Activin signaling mediates muscle-to-adipose communication in a mitochondria dysfunction-associated obesity model

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